Finally, under conditions where the spindle integrity checkpoint was experimentally induced, ZM blocked the establishment, but not the maintenance, of the checkpoint, at a point upstream of the checkpoint protein Mad2.These results show that Aurora kinase activity is required to ensure the maintenance of condensed chromosomes, the generation of chromosome-induced spindle microtubules, and activation of the spindle integrity checkpoint.Mitosis, the process by which a eukaryotic cell separates a complete copy of its duplicated genome into two identical sets in two daughter cells, is an extremely complex and tightly regulated process .
We exploited a hypermutagenic cancer cell line to select mutations conferring resistance to a well-studied Aurora inhibitor, ZM447439.
All resistant clones contained dominant point mutations in .
Aurora kinases have emerged as potential targets in cancer therapy, and several drugs are currently undergoing preclinical and clinical validation.
Whether clinical resistance to these drugs can arise is unclear.
Defects in mitotic signaling pathways, including those involving tubulin dynamics, might lead to unrestrained growth, one of the hallmarks of cancer cells.
The effectiveness of the taxanes and Vinca alkaloids in the treatment of many tumor types indicates the significance of the mitotic/tubulin machinery as a validated drug target [3, 4].Here, we have used extracts of eggs, which normally proceed through the early embryonic cell cycles in the absence of functional checkpoints, to distinguish between ZM's effects on the basic cell cycle machinery and its effects on checkpoints.ZM clearly had no effect on either the kinetics or amplitude in the oscillations of activity of several key cell cycle regulators.As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells.Moreover, these antimitotic drugs are also highly selective and sensitive.Several small molecules targeting aurora kinases A and B or both have been evaluated preclinically and in early phase I trials.